Chronic infection with the hepatitis C virus (HCV) is a major cause of cirrhosis, decompensated liver disease and hepatocellular carcinoma (HCC) worldwide. Globally there are an estimated 170 million persons with HCV. In the United States (U.S.), there are 4.1 million persons who are anti-HCV positive, 3.2 million of whom have chronic infection based on the detection of HCV RNA in serum. In 2001, chronic liver disease was the 12th leading cause of death in the U.S. These figures underscore the magnitude and impact that chronic HCV infection has on global and US public health. The natural history of chronic HCV infection is poorly understood. The protracted and silent course of infection, the absence of large cohorts of persons known to be infected, and the wide variability in outcome are major obstacles to natural history studies. Five to twenty-five percent of HCV-infected persons will develop cirrhosis over a 25-30 year period but some patients remain asymptomatic, without significant liver disease for many decades if not for life. Knowledge of the rate of progression among individuals who have not developed cirrhosis is unknown. An equally important and related issue is the clinical assessment of disease severity. Unfortunately, there are no good laboratory markers of disease severity. Liver biopsy is the accepted gold standard for assessing disease severity and cirrhosis but is costly, invasive, and associated with complications, which often limits patient acceptability as well as being subject to sampling error ranging from 15-25%. Non-invasive methods to assess disease severity are highly desirable for the clinicians diagnostic toolbox. The optimal treatment for chronic HCV infections results in sustained eradication of the virus in 54-56% of persons. It is evident that a large number of persons do not respond to therapy. The current state of therapy is inadequate, expensive, and cannot be applied to a substantial proportion of affected individuals due to problematic side effects. Therapeutic options for non-responder patients and persons who do not qualify for interferon-based regimens are limited. Thus newer, safer and more effective therapies are urgently needed for chronic HCV infection. Hypotheses/problems addressed: 1) Define the host, viral and environmental factors that determine the natural history and outcome of HCV infection. To address this problem, we have created a large database of untreated patients with chronic HCV (n700) and have analyzed this database to identify factors that affect the natural history of chronic HCV infection. Using this database, we have already reported on rates of fibrosis progression in untreated patients with chronic HCV infection and that hepatic steatosis does not appear to be a risk factor for progression of fibrosis in patients with chronic HCV infection. More recently, the database was used to search for candidate genes that were associated with fibrosis progression using a genetic haplotype approach. Among 18 haplotypes that occurred with a frequency >or=5% in the cohort overall, the Mx1-(-123C)-(+6886A)-(+19820G(379V))-(+38645T) (abbreviated Mx1-CAGT), and PKR-(+110T)-(+7949G)-(+13846A)-(+22937T)-(+40342T) (abbreviated PKR-TGATT) haplotypes were independently associated with less severe hepatic fibrosis (Ishak >or= 3 versus <3). To further define factors associated with fibrosis progression, we plan to analyze a large, well characterized cohort of over 1000 patients participating in a randomized, controlled, multi-center trial of long-term peginterferon versus no therapy for patients with advanced HCV infection (HALT-C-see below) We have already developed a simple model to predict cirrhosis. To extend on this, we plan to compare the baseline and year 4 liver biopsies from the untreated patients to prospectively identify clinical factors associated with progression of fibrosis. Finally, we are validating the usefulness of a new technology, ultrasound elastography (Fibroscan), to non-invasively assess hepatic fibrosis. Results of the Fibroscan will be compared to liver biopsy, MRI elastography and plasma will be stored for future proteomic analysis. Our goal is to develop a series of blood and imaging test that will obviate the need for liver biopsy in most patients with chronic HCV infection. 2) Develop and evaluate novel, safer and more effective therapies for chronic viral hepatitis. Though therapy of chronic HCV infection has improved over the last decade, it remains sub-optimal. Recent studies suggest that monitoring viral kinetics can be used to tailor therapy for individual patients, especially those who are difficult to treat such as those with genotype 1 infection and high viral load. Early viral kinetics can be used to shorten the course of therapy and to discontinue therapy early in patients who are unlikely to respond. In study 02-DK-0065, we are examining the effect of two different regimens of pegylated interferon alfa 2a plus ribavirin compared to the standard regimen on viral kinetics in patients with chronic HCV infection. We are studying the effect of ribavirin only as well as twice weekly versus once weekly dosing of peginterferon alfa-2a on viral kinetics. In addition we are studying the viral kinetics in special populations of patients with chronic HCV infection, namely those with renal failure. These studies are in progress. Therapy of non-responders with advanced hepatitis C is problematic. One approach to prevent disease progression in non-responder patients with chronic HCV infection is to use long-term therapy with anti-fibrotic effects. Limited clinical and in vitro data suggest that interferon alfa may slow or arrest progression of injury-related fibrosis, even in non-responders who fail to clear virus. The LDB is one of 10 sites participating in a large NIH sponsored multicenter study, the HALT-C Trial: a randomized controlled trial to evaluate the safety and efficacy of long-term peginterferon alfa-2a for treatment of chronic HCV infection in patients who fail to respond to previous interferon therapy. One thousand and fifty patients have been enrolled and the main trial results will be released in November, 2007. Elucidate the viral pathogenesis of chronic HCV infection and mechanisms of action of anti-viral therapy The conduct of clinical trials over the last 30 years has allowed the LDB to acquire invaluable clinical material (patient serum, liver tissue and lymphophocytes) to which state of the art laboratory techniques can be applied to address issues of the pathogenesis of HCV infection and the mechanisms of action of antiviral therapy. Ribavirin a guanosine nucleoside analogue has significantly improved the response rate to therapy in chronic hepatitis C, however its mechanism of action is unknown. Error catastrophe and lethal mutagenesis due to an increase in the viral mutation rate has been shown to be a possible mechanism of ribavirin in poliovirus, bovine diarrhea virus and GBV-B, viruses very similar to HCV. We hypothesized that error catastrophe and lethal mutagenesis may be the major mechanism of action of ribavirin in chronic HCV infection. We utilized stored sera collected at baseline, and weeks 4 and 24 from patients participating in a randomized, double blind, placebo controlled trial of ribavirin conducted in 1992-93 for this analysis. This study found that ribavirin is associated with an early, transient increase in the mutation rate of HCV but this effect was not seen later. This suggests that lethal mutagenesis and error catastrophe is unlikely to be the sole mechanism of action of ribavirin during therapy for chronic HCV infection. We plan to extend this investigation, examining higher doses of ribavirin and the effects of the combination of ribavirin and interferon on viral mutation rate.